The present invention relates to propiolophenone derivatives. In particular, it is concerned with propiolophenone derivatives of the formula ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently hydrogen, halogen, lower alkyl, lower alkoxy-lower-alkyl, hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkoxy-lower alkoxy, acyloxy, aryl-lower-alkoxy, lower alkylthio, lower alkoxy-lower-alkylthio, lower alkenylthio, lower alkynylthio, aryl lower-alkylthio, optionally substituted amino or trifluoromethyl, or two of these substituents which are adjacent jointly and together with the carbon atoms to which they are attached form a 5- to 7-membered ring, provided that of the substituents R.sup.1 to R.sup.5 at least two are hydrogen and at least one is different from hydrogen; and R6 is hydrogen, lower alkyl or a residue of the formula ##STR5## R.sup.7 is hydrogen, lower alkyl, lower alkenyl, lower alkoxy-lower-alkyl, lower alkoxy-lower-alkoxy-lower-alkyl, aryl or aryl-lower-alkyl; R.sup.8 and R.sup.9 are independently hydrogen or lower alkyl, or jointly and together with the nitrogen atom form a 5- to 7-membered saturated heterocyclic group; R.sup.10 is hydrogen, lower alkyl, aryl or aryl-lower-alkyl; R.sup.11 is hydrogen, lower alkyl, aryl or aryl-lower-alkyl; R.sup.12 is lower alkyl or lower alkoxy-lower-alkyl; R.sup.13 is lower alkyl; R.sup.14 and R.sup.15 are independently hydrogen, lower alkyl, aryl or aryl-lower-alkyl; and R.sup.16 is hydrogen, lower alkyl, lower alkoxy- lower-alkyl, lower alkenyl, lower alkynyl, acyl or aryl-lower-alkyl; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids.
These compounds are novel with the exception of:
4-methoxy-1-(3-methylphenyl)- 2-butyn-1-one; PA0 4-methoxy-1-(4-methoxyphenyl)-4-methyl-2-pentyn-1-one; PA0 4-methoxy-4 methyl-1-(3-methylphenyl)-2-pentyn- 1 one; PA0 methyl 3-(2,6-dimethoxybenzoyl)propiolate and PA0 N,N-diisopropyl- 3-(2-hydroxy-5-methylbenzoyl)propiolaide, PA0 -hydroxy 1-(3,4,5 -trimethoxyphenyl)-2-butyn-1-one; PA0 3-(4-methoxybenzoyl)propiolic acid; PA0 methyl 3-(2,3,4-trimethoxybenzoyl)propiolate; PA0 methyl 3-(4-hydroxybenzoyl)propiolate; PA0 2-(2-methoxyethoxy)ethyl 3-(3,4,5 -trimethoxybenzoyl)propiolate; PA0 2-(2-methoxyethoxy)ethyl 3-(4-methoxybenzoyl)propiolate; PA0 methyl 3-(2,5-dimethoxybenzoyl)propiolate; PA0 3-(2,5-dimethoxybenzoyl)propiolic acid; and PA0 2-(2-methoxyethoxy)ethyl 3-[3,4 -(methylenedioxy)-benzoyl]propiolate. PA0 3-(2,3,4 -trimethoxybenzoyl)propiolic acid; PA0 3-(3,4,5-trimethoxybenzoyl)propiolic acid: PA0 methyl 3-(4-fluorobenzoyl)propiolate; PA0 methyl 3-(3,4,5 -trimethoxybenzoyl)propiolate; PA0 N,N-dimethyl-3-(3,4,5-trimethoxybenzoyl)propiolamide; PA0 1-(4-fluorophenyl)-4-hydroxy-2-butyn-1-one; PA0 4-hydroxy-1-(4-methylphenyl)-2-butyn-1-one; PA0 4-(1-ethoxyethoxy)-1-(4-fluorophenyl)-2-butyn-1-one; PA0 1-(4-chlorophenyl)-4-hydroxy-2-butyn-1-one; PA0 4-hydroxy-1-(4-methoxyphenyl)-2-butyn-1-one PA0 4-hydroxy-1,3,4 methylenedioxy)phenyl]-2-butyn-1-one; PA0 4-hydroxy-1-3,4,5 -trimethoxyphenyl)-2-pentyn-1-one; PA0 4-(1-ethoxyethoxy)-1-(2,3,4-trimethoxyphenyl)-2 butyl-1-one; PA0 4-hydroxy-1-(2,3,4-trimethoxyphenyl)-2-butyn-1-one; and PA0 4-hydroxy-I-[4-(methylthio)phenyl]-2-butyn- 1-one. PA0 ethyl 4-(2,5-dimethoxyphenyl)-4-hydroxy-2-butynoate; PA0 ethyl 4-(2-methoxyphenyl)-4-hydroxy-2-butynoate; PA0 methyl 4-(2-benzyloxy-6-methoxyphenyl)-4-hydroxy-2 -butynoate; PA0 4 (2-benzyloxy-6-methoxyphenyl- 4- -hydroxy-2-butynoic acid: and PA0 4-(2,6-dimethoxyphenyl)-4-hydroxy-2-butynoic acid.
and it has been found that they possess valuable pharmacodynamic properties, namely mucosa-protective and/or gastric acid secretion-inhibiting properties, such that they can be used for the control or prevention of illnesses of the gastrointestinal tract, especially against gastric ulcers and/or duodenal ulcers.
Aspects of the present invention comprise the compounds and salts defined earlier as therapeutically active substances, medicaments containing such a compound or a salt thereof, and the use of the compounds and salts defined earlier in the control or prevention of illnesses, especially in the control or prevention of gastric ulcers and/or duodenal ulcers.
The term "lower" denotes compounds or residues with a maximum of 7, preferably a maximum of 4, carbon atoms.
The term "alkyl" denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-butyl and the like. The terms "alkoxy" and "alkylthio" denote alkyl groups in the sense of the previous definition attached via an oxygen atom and a sulphur atom, respectively, such as methoxy and methylthio, respectively, and the like. The terms "alkenyl" and "alkynyl" denote hydrocarbon groups which contain a carbon-carbon double or triple bond, for example, groups such as dimethylallyl. The term "aryl" denotes an optionally substituted phenyl group such as 4-methoxyphenyl, 3,4-methylenedioxyphenyl-2,4,6-trimethylphenyl, 3,4,5-trimethoxyphenyl and the like. The term "acyl" embraces lower alkanoyl groups such as acetyl or the like and aroyl groups (i.e., arylcarbonyl groups) such as 3,4,5-trimethoxybenzoyl and the like. The term "halogen" embraces the four forms: chlorine, fluorine, bromine and iodine. The term "optionally substituted amino" denotes an amino group which can be monosubstituted by lower alkyl or acyl or disubstituted by lower alkyl and acyl or by two lower alkyl residues.
The 5- to 7-membered ring which two adjacent substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 together With the carbon atoms to which they are attached can form can be heterocyclic or carbocyclic. This ring can optionally contain one or more additional double bonds, in which case it can be aromatic or non-aromatic, and the ring can be substituted or unsubstituted. The 5- to 7-membered saturated heterocyclic residue which R.sup.8 and R.sup.9 together with the nitrogen atom can form can contain an additional hetero atom and it can be substituted or unsubstituted.
For example, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 can independently be hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, lower alkylthio or di-lower alkylamino or two of these substituents which are adjacent can together be lower alkylene or lower alkylenedioxy, provided that of the substituents R.sup.1 to R.sup.5 at least one is different from hydrogen and at least two are hydrogen, preferably R.sup.1 is hydrogen.
Preferably, in formula I R.sup.1 and R.sup.2 are hydrogen and R.sup.3 R.sup.4 and R.sup.5 are lower alkoxy; or R.sup.1 and R.sup.5 are hydrogen and R.sup.2, R.sup.3 and R.sup.4 are lower alkoxy; or R.sup.1, R.sup.3 and R.sup.4 are hydrogen and R.sup.2 and R.sup.5 are lower alkoxy; or R.sup.1, R.sup.2 and R.sup.5 are hydrogen and R.sup.3 and R.sup.4 together are lower alkylenedioxy or lower alkylene; or R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen and R.sup.3 is halogen, lower alkyl, hydroxy, lower alkoxy, lower alkylthio or di-lower alkylamino; R.sup.6 is a residue of formula (a), (b), (c), (d), (e) or (f) in which R.sup.7 is hydrogen, lower alkyl, lower alkoxy-lower-alkoxy-loweralkyl, aryl-lower alkyl or lower alkenyl, R.sup.8 and R.sup.9 are lower alkyl, is hydrogen, R.sup.11 is hydrogen, R.sup.12 is lower alkyl, R.sup.13 is lower alkyl, R.sup.14 is hydrogen, R.sup.15 is hydrogen or lower alkyl and R.sup.16 is hydrogen, lower alkenyl, lower alkoxy-lower-alkyl or acyl.
Among the compounds of formula I there are especially preferred those in which R.sup.1 and R.sup.2 are hydrogen and R.sup.3, R.sup.4 and R.sup.5 are methoxy, or R.sup.1 and R.sup.5 are hydrogen and R.sup.2, R.sup.3 and R.sup.4 are methoxy, or R.sup.1, R.sup.3 and R.sup.4 are hydrogen and R.sup.2 and R.sup.5 are methoxy, or R.sup.1, R.sup.2 and R.sup.5 are hydrogen and R.sup.3 and R.sup.4 together are methylenedioxy, or R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen and R.sup.3 is chlorine, fluorine, methyl, hydroxy, methoxy or methylthio, and in which R.sup.6 is a residue of formula (a), (b) or (f) in which R.sup.7 is hydrogen, methyl or methoxyethoxyethyl, R.sup.8 and R.sup.9 each is methyl, R.sup.14 is hydrogen, R.sup.15 is hydrogen or methyl and R.sup.16 is hydrogen or 1-ethoxyethyl.
3-[3,4-(Methylenedioxy)benzoyl]propiolic acid is a particularly preferred compound of formula I.
Additional especially preferred compounds of formula I are:
Further preferred compounds of formula I are:
The novel propiolophenone derivatives of formula I defined earlier and their salts can be prepared by the following procedures:
(a) oxidizing a compound of the formula ##STR6## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the above mentioned meanings and R.sup.6 ' is hydrogen lower alkyl, a group of formula (a), (b), (c), (d) or (e) or a group of the formula EQU --C(R.sup.14)(R.sup.15)OR.sup.16' (f')
in which R.sup.14 and R.sup.15 have the above mentioned meanings and R.sup.16 ' is as defined above for R.sup.16 but hydrogen when R.sup.14 and/or R.sup.15 are hydrogen;, or
(b) cleaving off the protecting group(s) from a compound of the formula ##STR7## wherein R.sup.1', R.sup.2 ', R.sup.3 ', R.sup.4 ' and R.sup.5 ' have the meanings given above for R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 and a maximum of three of them can additionally represent protected hydroxy, protected amino or protected lower alkylamino, R.sup.6" is a residue of formula (a), (b), (c), (d), (e) or EQU --C(R.sup.14)(R.sup.15)OR.sup.16" (f")
in which R.sup.14 and R.sup.15 have the above meanings and R.sup.16" has the same meaning given above for R.sup.16 and can additionally represent a protecting group, whereby the molecule contains at least one protecting group; or
(c) reacting a compound of the formula ##STR8## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above and R.sup.17 is a leaving group, with a compound of the formula EQU HC.tbd.C--R.sup.6"' V
wherein R.sup.6 "' is a group of formula (a), (b), (d), (e) or (f);
(d) cleaving a compound of formula I in which R.sup.6 is a group of formula (a) wherein R is different from hydrogen, to the corresponding carboxylic acid, or
(e) acylating a compound of formula I in which R.sup.6 is a group of formula (f) in which R.sup.16 is hydrogen; or
(f) converting a compound of formula I in which R.sup.6 is a group of formula (d) into the corresponding compound of formula I in which R.sup.6 is a group of formula (c); or
(g) converting an acidic compound of formula I with a base or a basic compound of formula I with an acid into a pharmaceutically acceptable salt.
The compounds of formula II have similar pharmacodynamic properties to the propiolophenone derivatives of formula 1, primarily those in which R.sup.6 ' is a group of formula (a) above in which R.sup.7 is especially lower alkyl or lower alkoxy-lower-alkoxy-lower-alkyl.
Representative examples of such compounds are: methyl 4-hydroxy-4-[3,4-(methylenedioxy)-phenyl]-2-butynoate and 2-(2-methoxyethoxy)ethyl4-hydroxy-4-(3,4,5 -trimethoxyphenyl)-2-butynoate.
The compounds of formula II are novel with the exception of
A further aspect of the present invention is. accordingly, compounds of formula II which are useful as therapeutically active substances, pharmaceutical compositions containing such a compound, and the use of such compounds of formula II in the control or prevention of illnesses, especially in the control or prevention of gastric ulcers and/or duodenal ulcers.
Preferably, in formula II R.sup.1 and R.sup.2 each are hydrogen and R.sup.3, R.sup.4 and R.sup.5 each are lower alkoxy, or R.sup.1 and R.sup.5 each are hydrogen and R.sup.2, R.sup.3 and R.sup.4 each are lower alkoxy, or R.sup.1, R.sup.2 and R.sup.5 each are hydrogen and R.sup.3 and R.sup.4 together are lower alkylenedioxy or lower alkylene, or R.sup.1, R.sup.2, R.sup.4 and R.sup.5 each are hydrogen and R.sup.3 is halogen, lower alkyl, hydroxy, lower alkoxy, lower alkylthio or di-lower alkylamino.
The novel compounds of formula II can be prepared by the following procedures:
(aa) reacting a compound of the formula ##STR9## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above,
with a compound of the formula EQU HC.tbd.C--R.sup.6iv Va
wherein R.sup.6iv is a group of formula (a), (b), (d), (e) or (f'); or
(bb) cleaving off the protecting group(s) from a compound of the formula ##STR10## wherein R.sup.1', R.sup.2', R.sup.3', R.sup.4' and R.sup.5' are as defined above, R.sup.6v is a group of formula (a), (b) or (c) or a residue of the formula EQU --C(R.sup.14)(R.sup.15)OR.sup.16"' (f"')
in which R.sup.7 and R.sup.10 are different from hydrogen, R.sup.14 and R.sup.15 have the meanings given in formula 1 and R.sup.16"' has the meaning given for R.sup.16' in formula II, except, however, R.sup.16"' can additionally be a protecting group, and R.sup.18 is a protecting group.
The oxidation in accordance with process variant (a) is effected under methods which are known and familiar to those skilled in the art of converting a hydroxy group into an oxo group. As the oxidation agent there can be used manganese dioxide (pyrolusite) in a suitable solvent which is inert under the reaction conditions, for example, a halogenated hydrocarbon such as methylene chloride or the like. The oxidation by means of manganese dioxide is conveniently effected in a temperature range of about 0.degree. C. to about room temperature and takes about 10 minutes to about 20 hours, depending on the other reaction conditions. If R.sup.6' in formula II is a residue of formula (c) in which R.sup.10 is hydrogen, then, depending on the reaction conditions, oxidation to a residue of formula (a) in which R.sup.7 is hydrogen can be effected.
Suitable protecting groups in the compounds of formula III which are used as starting materials in process variant (b) are, of course, only those which can be cleaved off by methods which selectively remove these protecting groups without affecting other structural elements present in the molecule. The removal of the protecting group or groups from the compounds of formula III is effected according to methods known per se. As those skilled in the art will understand, the nature of the protecting group or groups must be taken into consideration when choosing the method to be used and care must be taken that only the protecting group or protecting groups is/are selectively removed without affecting other structural elements present in the molecule. Suitable O-protecting groups are, for example, readily cleavable acetal and ketal protecting groups such as methoxymethyl, methoxyethoxymethyl, 1-ethoxyethyl, 2-(trimethylsilyl)-ethoxymethyl, -tetrahydro- 2H-pyran-2-yl and the like; readily cleavable metal-organic groups, especially trialkylsilyl groups such as trimethylsilyl, t-butyldimethylsilyl and the like; readily cleavable aralkyl groups such as triphenylmethyl and the like; readily cleavable acyl groups such as acetyl and the like; etc. Suitable N-protecting groups are primarily readily cleavable acyl groups such as t-butyloxycarbonyl and the like.
Methods for the removal of the residues which have been mentioned hereinbefore as examples of protecting groups are described in the literature and are accordingly, familiar to any person skilled in the art. Thus, for example, the methoxymethyl group, the methoxyethoxymethyl group, the 1-ethoxyethyl group, the 2-(trimethylsilyl)-ethoxymethyl group, the tetrahydro-2H-pyran-2-yl group, the trimethylsilyl group, the t-butyldimethylsilyl group and the triphenylmethyl group can be cleaved off under acidic conditions, for example, by means of aqueous hydrochloric acid in an organic solvent which is inert under the reaction conditions, such as tetrahydrofuran. The tetrahydro-2H-pyran-2-yl group, the trimethylsilyl group and the t-butyldimethylsilyl group can, however, also be cleaved off conveniently by means of pyridinium p-toluene sulphonate in an organic solvent or solvent mixture which is inert under the reaction conditions, such as tetrahydrofuran/ethanol. The trimethylsilyl group and the t-butyldimethylsilyl group can also be cleaved off by means of a guaternary ammonium fluoride such as tetrabutylammonium fluoride in an organic solvent which is inert under the reaction conditions, such as tetrahydrofuran. The acetyl group can be cleaved off under mild alkaline conditions, for example, by means of dilute (about 2-5%) potassium hydroxide solution in an organic solvent which is inert under the reaction conditions, such as tetrahydrofuran. The cleavage of a t-butyloxycarbonyl group can be effected under acidic conditions, for example, by means of an aqueous acid or anhydrous trifluoroacetic acid.
Suitable leaving groups (R.sup.17) in the compounds of formula IV which are used as starting materials in process variant (c) are primarily groups such as N-methoxy-N-methylamino and the like. The reaction of the compounds of formulae IV and V is effected in the presence of a strong base such as butyllithium, alkylmagnesium halides (e.g., ethylmagnesium bromide) and the like, in an organic solvent or solvent mixture which is inert under the reaction conditions, for example, in tetrahydrofuran/hexamethylphosphortriamide. Furthermore, the reaction is conveniently effected at a temperature of about -80.degree. to about room temperature and takes about 1 hour to about 3 hours.
The ester cleavage in accordance with process variant (d) is effected according to methods which are known and are familiar to those skilled in the art, and conveniently by hydrolysis using a strong inorganic base, for example, an alkali metal hydroxide such as potassium hydroxide or the like, in a suitable solvent system, for example, in water or aqueous tetrahydrofuran and the like. When R.sup.7 is a benzyl residue which is readily cleavable under acidic conditions, such as 4-methoxybenzyl, 3,4-methylenedioxybenzyl, 2,4,6-tri-methylbenzyl or the like, then the ester cleavage can also be effected by means of trifluoroacetic acid (in the presence or absence of a solvent such methylene chloride, anisole or the like). by means of formic acid, by means of hydrogen bromide in glacial acetic acid, or by means of analogous reagents.
The acylation in accordance with process variant (e) is also effected according to known methods. As the acylation agent there is used, for example, an acid halide which corresponds to the acyl residue to be introduced, such as acetyl chloride, 3,4,5-trimethoxybenzoyl chloride and the like. The acylation by means of such an acid halide is conveniently effected in the presence of a base, especially a tertiary organic base such as pyridine, triethylamine, N-methylpiperidine, 4-dimethylaminopyridine or the like. Suitable solvents are primarily halogenated hydrocarbons such as methylene chloride or the like. When pyridine is used as the base, then this base can simultaneously also serve as the solvent. If one or more of R.sup.1 -R.sup.5 represents a hydroxy group and/or an amino group and/or a lower alkylamino group, then they are likewise acylated.
In accordance with process variant (f), an acetal or ketal group is converted into a carbonyl group. This is effected according to established methods which are familiar to those skilled in the art, and conveniently by means of aqueous perchloric acid or the like, in an organic solvent which is inert under the reaction conditions, such as dioxane or the like, at about room temperature and takes a few (for example, 2) hours.
The conversion of an acidic compound of formula I into a pharmaceutically usable salt can be carried out by treatment with a suitable base in a known manner. As such salts there are suitable not only those with cations derived from an inorganic base, e.g., potassium salts, sodium salts, calcium salts and the like, but also salts with organic bases such as ethylenediamine, monoethanolamine, diethanolamine and the like.
The conversion of a basic compound of formula I into a pharmaceutically usable salt can be carried out by treatment with a suitable acid. As such salts there are suitable not only those with inorganic acids such as hydrogen chloride, hydrogen bromide phosphoric acid, sulphuric acid and the like, but also salts with organic acids such as citric acid, malic acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
The preparation of compounds of formula II in accordance with process variant (aa) is effected in the presence of a strong base such as butyllithium, alkylmagnesium halides (e.g., ethylmagnesium bromide) and the like, in an organic solvent or solvent mixture which is inert under the reaction conditions, for example, in tetrahydrofuran/n-hexane, tetrahydrofuran/diethyl ether/n-hexane and the like. The reaction temperature is preferably in the range from about -120.degree. to about room temperature, with the choice of the reaction temperature depending, inter alia, on the solvent or solvent mixture which is used. The reaction time is about 1-2 hours. The compounds of formula Va can be used in free form or in the form of reactive derivatives, conveniently in the form of tri-lower-alkylsilyl derivatives, such as trimethylsilyl derivatives. Examples of suitable compounds of formula Va or reactive derivatives thereof are: 1-(1-ethoxyethoxy)-2-propyne, methyl propiolate, propiolic acid, 3,3-diethoxy-1-propyne, 3-butyn-2-ol, ethyl propiolate. 1-[(3-methyl-2-butenyl)oxy]-2-propyne, triethyl 3-trimethylsilyl-orthopropiolate, and so forth.
Suitable protecting groups (R.sup.18) in the compounds of formula VII which are used as starting materials in accordance with process variant (bb) are primarily readily cleavable metal-organic groups such as trimethylsilyl, t-butyldimethylsilyl and the like. Such residues are conveniently cleaved off by means of aqueous acid, for example, aqueous hydrochloric acid, in an organic solvent which is inert under the reaction conditions, such as ethyl acetate, dioxane or the like. The cleavage of such groups can, however, also be effected by means of pyridinium p-toluenesulphonate or a quaternary ammonium fluoride such as tetrabutylammonium fluoride.
The preparation of the starting materials of formula III can be carried out by analogy to the preparation of the corresponding compounds of formula I.
The starting materials of formulae IV, V and VI are available or can be prepared readily according to methods which are known to those skilled in the art. Moreover, many of the Examples hereinafter contain detailed information concerning the preparation of certain compounds of formula V.
The starting materials of formula VII can be prepared, for example, by reacting a compound of the formula ##STR11## wherein R.sup.1', R.sup.2', R.sup.3', R.sup.4', R.sup.5' and R.sup.18 are as defined above,
in the presence of a strong base such as n-butyllithium or the like, in an organic solvent or solvent mixture which is inert under the reaction conditions, such as ether/n-hexane, tetrahydrofuran/n-hexane or the like, with a compound of the formula EQU X--R.sup.6iv IX
wherein R.sup.6iv has the above meaning and X is a leaving group (especially chlorine),
for example, with butyl chloroformate, N,N-dimethylcarbamoyl chloride or the like.
The preparation of the starting materials of formula VIII is effected according to methods which are known to those skilled in the art from corresponding compounds of the formula ##STR12## wherein R.sup.1', R.sup.2', R.sup.3', R.sup.4' and R.sup.5' have the above meanings, by introduction of the desired protecting group, for example, by means of trimethylsilyl chloride in the presence of n-butyllithium in ether/n-hexane, or by means of t-butyldimethylsilyl chloride in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene in methylene chloride. The starting materials of formulae IX and X are available or can be prepared according to methods which are known.
As mentioned earlier, the compounds of formulae I and II as well as pharmaceutically acceptable salts of compounds of formula I possess valuable pharmacodynamic properties, as already described herein.
Representative compounds of formulae I and II were investigated with respect to their mucosa-protective and gastric acid secretion-inhibiting properties, as well as for their toxicity.
The experimental procedure described hereinafter was used to determine the mucosa-protective property:
The oral administration of absolute ethanol to male rats in a dosage of 1 ml per rat leads within 1 hour to bloody lesions of the mucous membrane of the stomach. Various dosages of the substances to be tested (suspended in 0.125% carboxymethycellulose) or of the vehicle alone (control) are administered to the rats orally (1 ml per rat) 30 minutes prior to the treatment with ethanol. One hour after the administration of the ethanol the animals are killed, their stomachs are investigated for the presence of lesions and the number and the total dimension of such lesions are determined. The ID.sub.50 is that dosage of a test substance which reduces by 50% the number of lesions in comparison to the control group.
The test procedure described hereinafter was used to determine the gastric acid secretion-inhibiting activity:
The pylorus of male rats is ligated under slight ether narcosis in accordance with Shay et al., Gastroenterology 5. 43 (1945). The substances to be tested, suspended in 0.5% carboxymethylcellulose, are administered intraduodenally. Control animals are treated only with the vehicle. Five hours after the ligation the animals are killed, the volume and acidity of their gastric juice are determined and the values obtained are compared with those of control animals. The ID.sub.50 is that dosage of a test substance which brings about a 50% decrease of the secretion in comparison to the control animals. In the following Table there are given for a series of representative compounds of formula I and for two compounds of formula II the results of the testing with respect to their mucosa-protective activity ("ethanol test") and to their gastric acid secretion-inhibiting activity. Moreover, this Table contains data concerning the acute toxicity (LD.sub.50 in the case of single oral administration to mice).
______________________________________ Gastric acid secretion- Ethanol Test inhibition, Toxicity ID 50 ID 50 LD 50 Compound mg/kg p.o. mg/kg i.d. mg/kg p.o. ______________________________________ A 1.2 42 625-1250 B 1.9 18 156-312 C 1.4 -- 625-1250 D 2.1 -- 625-1250 E 1.2 -- 312-625 F 2.9 -- &gt;5000 G 2.1 -- 1000-2000 H 2.2 -- &gt;5000 I 1.9 -- 625-1250 J 2.3 &gt;100 1250-2500 K 3.4 -- 500-1000 L 4.1 56 1000-2000 M 4.2 -- 1250-2500 N 4.2 &gt;100 &gt;5000 O 2.8 28 312-625 P 0.9 -- 80-156 Q 1.5 -- 80-156 R 1.4 -- 80-156 S 1.2 -- 80-156 T 1.2 -- 40-80 U 1.1 -- 80-156 V 1.2 3.1 156-312 W 0.8 9 312-625 X 0.8 4.0 156-312 Y 1.0 2.7 156-312 Aa 1.4 -- 312-625 Bb 4.0 -- 625-1250 ______________________________________ A = 3[3,4(Methylenedioxy)benzoyl]propiolic acid B = 4Hydroxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one C = 3(4-Methoxybenzoyl)propiolic acid D = Methyl 3(2,3,4-trimethoxybenzoyl)propiolate E = Methyl 3(4-hydroxybenzoyl)propiolate F = 2(2-Methoxyethoxy)ethyl 3(3,4,5-trimethoxybenzoyl)-propiolate G = 2(2-Methoxyethoxy)ethyl 3(4-methoxybenzoyl)-propiolate H = Methyl 3(2,5-dimethoxybenzoyl)propiolate I = 3(2,5-Dimethoxybenzoyl)propiolic acid J = 2(2-Methoxyethoxy)ethyl 3[3,4(methylenedioxy)-benzoyl]propiolate K = 3(2,3,4-Trimethoxybenzoyl)propiolic acid L = 3(3,4,5-Trimethoxybenzoyl)propiolic acid M = Methyl 3(4-fluorobenzoyl)propiolate N = Methyl 3(3,4,5-trimethoxybenzoyl)propiolate O = N,NDimethyl-3-(3,4,5-trimethoxybenzoyl)propiolamide P = 1(4-Fluorophenyl)-4-hydroxy-2-butyn-1-one Q = 4Hydroxy-1-(4-methylphenyl)-2-butyn-1-one R = 4(1-Ethoxyethoxy)-1-(4-fluorophenyl)-2-butyn-1-one S = 1(4-Chlorophenyl)-4-hydroxy-2-butyn-1-one T = 4Hydroxy-1-(4-methoxyphenyl)-2-butyn-1-one U = 4Hydroxy-1-[3,4(methylenedioxy)phenyl2-butyn-1-one V = 4Hydroxy-1-(3,4,5-trimethoxyphenyl)-2-pentyn-1-one W = (1Ethoxyethoxy)-1-(2,3,4-trimethoxyphenyl)-2-butyn-1-one X = 4Hydroxy-1-(2,3,4-trimethoxyphenyl)-2-butyn-1-one Y = 4Hydroxy-1-[4(methylthio)phenyl2-butyn-1-one Aa = Methyl 4hydroxy-4-[3,4methylenedioxy)phenyl2-butynoate Bb = 2(2-methoxyethoxy)ethyl 4hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate.
The compounds of formulae I and II and the pharmaceutically acceptable salts of compounds of formula I can be used as medicaments, for example, in the form of pharmaceutical preparations. Oral administration of such compounds can be in the form of solid pharmaceutical preparations such as tablets, coated tablets, dragees, hard gelatine capsules and soft gelatine capsules. Oral administration in the form of liquid preparations such as solutions, emulsions and suspensions, rectal administration, e.g., suppositories, or parenteral administration, e.g. in the form of injection solutions, are also encompassed within the practice of this invention.
The preparation of medicaments of this invention can be effected by mixing one or more of the compounds of formula I or II or of the pharmaceutically usable salts of the compounds of formula I and, if desired, one or more other therapeutically active substances with one or more therapeutically inert excipients.
For the preparation of tablets, coated tablets, dragees and hard gelatine capsules in particular, the compounds of formulae I and II and the pharmaceutically usable salts of compounds of formula I can be processed with pharmaceutically inert, inorganic or organic excipients. As such excipients there can be used for tablets, dragees and hard gelatine capsules materials such as lactose, maize starch or derivatives thereof, talc, stearic acid or its salts, and so forth. For the preparation of pharmaceutical preparations which are resistant to gastric fluids it is necessary to apply a gastric fluid-resistant (enteric) coating which can consist of, for example, hydroxypropylmethylcellulose phthalate or other suitable material, as those skilled in the art will understand.
Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and so forth.
Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, and the like.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerine, vegetable oils, and so forth.
The pharmaceutical preparations can contain, in addition, preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formulae I and II and the pharmaceutically usable salts of compounds of formula I can be used in the control or prevention of illnesses, for example in the control or prevention of gastric ulcers and/or duodenal ulcers. The dosage can vary and, of course, will be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily administration of about 30-400 mg in single or divided doses, should be appropriate and in the case of intravenous administration a daily dosage of about 1-50 mg should be appropriate.